Hippocampal metaplasticity induced by deficiency in the extracellular matrix glycoprotein tenascin-R
Hippocampal metaplasticity induced by deficiency in the extracellular matrix glycoprotein tenascin-R
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DOI：
10.1523/jneurosci.1022-07.2007
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发表时间：
2007-05-30
影响因子：
5.3
通讯作者：
Dityatev, Alexander
中科院分区：
文献类型：
--
作者：
Bukalo, Olena;Schachner, Melitta;Dityatev, Alexander
突触经历可塑性变化的倾向可以根据突触活动的历史进行动态调整（即，例如，突触是化生的）。在寻找一个潜在的metaplasticity的分子机制，我们研究了小鼠缺乏糖蛋白tenascin-R（TNR），基于观察，这种突变体表现出升高的基础兴奋性突触传递和减少体周GABA能抑制。TNR是CNS的主要细胞外基质糖蛋白，并携带HNK-1碳水化合物（人自然杀伤细胞聚糖），其已被鉴定为介导通过GABA（B）受体调节GABA能传递的功能性表位。在这里，我们使用膜片钳记录在海马切片，以确定在CA 3-CA 1突触的长时程增强（LTP）诱导所需的突触后神经元去极化的临界水平，发现TNR的缺乏导致诱导LTP的阈值的化生增加。用HNK-1糖模拟物或GABA（A）受体激动剂、GABA（B）受体拮抗剂、L型电压依赖性Ca 2+通道阻滞剂或蛋白丝氨酸/苏氨酸磷酸酶抑制剂对TNR缺陷小鼠的切片进行重建，使LTP恢复到野生型小鼠的水平。我们提出，一系列事件开始减少GABA能传输和通过Ca 2+进入细胞和磷酸酶活性升高介导的稳态调节海马可塑性在TNR的情况下进行。这些数据揭示了一种新的机制，通过这种机制，细胞外基质分子及其相关的碳水化合物提供了有利于诱导海马CA 1区LTP的条件。
Predisposition of synapses to undergo plastic changes can be dynamically adjusted according to the history of synaptic activity (i. e., synapses are metaplastic). In search of a molecular mechanism underlying metaplasticity, we investigated mice deficient in the glycoprotein tenascin-R (TNR), based on the observations that this mutant exhibits elevated basal excitatory synaptic transmission and reduced perisomatic GABAergic inhibition. TNR is a major extracellular matrix glycoprotein of the CNS and carries the HNK-1 carbohydrate (human natural killer cell glycan), which has been identified as the functional epitope mediating regulation of GABAergic transmission via GABA(B) receptors. Here, we used patch-clamp recordings in hippocampal slices to determine the critical levels of postsynaptic neuron depolarization necessary for induction of long-term potentiation (LTP) at CA3-CA1 synapses and found that deficiency in TNR leads to a metaplastic increase in the threshold for induction of LTP. Reconstitution of slices from TNR-deficient mice with an HNK-1 glycomimetic or pharmacological treatment with either a GABA(A) receptor agonist, a GABA(B) receptor antagonist, an L-type voltagedependent Ca2+ channel blocker, or an inhibitor of protein serine/ threonine phosphatases restored LTP to the levels seen in wild-type mice. We propose that a chain of events initiated by reduced GABAergic transmission and proceeding via Ca2+ entry into cells and elevated activity of phosphatases mediates homeostatic adjustment of hippocampal plasticity in the absence of TNR. These data uncover a novel mechanism by which an extracellular matrix molecule and its associated carbohydrate provide conditions beneficial for induction of LTP in the CA1 region of the hippocampus.